Herpes simplex virus is the leading cause of infectious blindness in the USA and is an important disease world-wide. The incidence of ocular herpes is between 4.1 to over 20 cases per 100,000 persons, with about 20% of these developing the chronic inflammatory stromal disease. Recurrences of stromal disease can result in permanent scarring and loss of vision, so necessitating corneal transplantation. Human stromal keratitis (SK) is controlled by combination therapy that includes antivirals and steroid anti-inflammatory drugs. New forms of treatment would be useful. The disease in humans is considered to be immune mediated, as is certainly the case in animal models of SK. The most convenient animal model to study the pathogenesis of SK is primary ocular infection in immunocompetent mice strains. Studies with this model have revealed how virus infection sets off an inflammatory response that eventually becomes chronic, but a full understanding of SK pathogenesis is still lacking. This information is needed, since essential steps may be identified that can conveniently be manipulated to control the extent of disease. This proposal has 3 specific aims, two of which deal with aspects of SK pathogenesis, and the third aim is designed to evaluate various means of therapy, given singly or in combination. Aim 1: will be to evaluate immune stimulating events by HSV focusing on toll-like receptor ligands produced by the virus as well as viral antigen effects. Aim 2: will be to further define the specificity characteristics and cytokine producing properties of T cells that orchestrate SK in immunocompetent and compromised mice. These experiments should evaluate the participation of non-HSV specific bystander T cells in SK lesions as well as the role of cytokines driven by IL-12 or IL-23. Aim 3: is designed to evaluate several novel treatment approaches given at different times after infection given alone or in concert with antiangiogenesis approaches to control the severity of SK. This grant is designed to understand how infection of the eye with herpes simplex virus results in a blinding immunoinflammatory reaction in the normally transparent cornea. We propose that identifying key molecular and cellular events that occur which could result in the design of novel means of therapy. The research will also evaluate several novel treatment regimens used alone or in combination to control the severity of the corneal inflammation in an experimental mouse model.